clinical sensitivity of molecular genetic testing in hypertrophic cardiomyopathy. kate thomson...
TRANSCRIPT
![Page 1: Clinical sensitivity of molecular genetic testing in hypertrophic cardiomyopathy. Kate Thomson Molecular Genetics Laboratory, Oxford](https://reader035.vdocument.in/reader035/viewer/2022070307/551b3117550346cf5a8b60f1/html5/thumbnails/1.jpg)
Clinical sensitivity of molecular genetic testing
in hypertrophic cardiomyopathy.
Kate ThomsonMolecular Genetics Laboratory,
Oxford
![Page 2: Clinical sensitivity of molecular genetic testing in hypertrophic cardiomyopathy. Kate Thomson Molecular Genetics Laboratory, Oxford](https://reader035.vdocument.in/reader035/viewer/2022070307/551b3117550346cf5a8b60f1/html5/thumbnails/2.jpg)
Overview
• Hypertrophic Cardiomyopathy– Clinical features– Genetics
• Clinical sensitivity in our cohort
• Factors affecting clinical sensitivity
![Page 3: Clinical sensitivity of molecular genetic testing in hypertrophic cardiomyopathy. Kate Thomson Molecular Genetics Laboratory, Oxford](https://reader035.vdocument.in/reader035/viewer/2022070307/551b3117550346cf5a8b60f1/html5/thumbnails/3.jpg)
• Characterised by thickening of the heart muscle, most commonly of the left ventricle, with no obvious cause (e.g. high blood pressure, athletes heart)
• Autosomal Dominant
• Prevalence of 1/500
• Most common cause of heart related sudden death in people under 35 and athletes
Hypertrophic cardiomyopathy
![Page 4: Clinical sensitivity of molecular genetic testing in hypertrophic cardiomyopathy. Kate Thomson Molecular Genetics Laboratory, Oxford](https://reader035.vdocument.in/reader035/viewer/2022070307/551b3117550346cf5a8b60f1/html5/thumbnails/4.jpg)
The hypertrophic heart
![Page 5: Clinical sensitivity of molecular genetic testing in hypertrophic cardiomyopathy. Kate Thomson Molecular Genetics Laboratory, Oxford](https://reader035.vdocument.in/reader035/viewer/2022070307/551b3117550346cf5a8b60f1/html5/thumbnails/5.jpg)
Clinical Features• Clinically heterogeneous
-No symptoms-Shortness of breath-Chest pain-Fainting-Dizziness-Palpitations-Exercise intolerance-Sudden death
• Variable presentation, age of onset and clinical course
• Differential diagnoses: -Cardiac amyloidosis-Hypertensive heart disease-Aortic stenosis-Athletes heart-Metabolic disease (Fabry’s disease, Danon disease)-Mitochondrial myopathy
![Page 6: Clinical sensitivity of molecular genetic testing in hypertrophic cardiomyopathy. Kate Thomson Molecular Genetics Laboratory, Oxford](https://reader035.vdocument.in/reader035/viewer/2022070307/551b3117550346cf5a8b60f1/html5/thumbnails/6.jpg)
Benefits of Genetic Diagnosis
• Confirm clinical diagnosis/familial disorder
• Offer testing to at risk family members to enable early diagnosis and treatment
• Future – Risk stratification and prognosis – Patient management
![Page 7: Clinical sensitivity of molecular genetic testing in hypertrophic cardiomyopathy. Kate Thomson Molecular Genetics Laboratory, Oxford](https://reader035.vdocument.in/reader035/viewer/2022070307/551b3117550346cf5a8b60f1/html5/thumbnails/7.jpg)
Genetics
• >20 genes known to be associated
• Majority of genes encode components of the sarcomere (contractile apparatus of the heart)
• Four genes commonly associated sarcomeric genes account for ~80% of mutations.
• Double/compound variants reported in 5-10%
![Page 8: Clinical sensitivity of molecular genetic testing in hypertrophic cardiomyopathy. Kate Thomson Molecular Genetics Laboratory, Oxford](https://reader035.vdocument.in/reader035/viewer/2022070307/551b3117550346cf5a8b60f1/html5/thumbnails/8.jpg)
Cardiac muscle cell & sarcomere
![Page 9: Clinical sensitivity of molecular genetic testing in hypertrophic cardiomyopathy. Kate Thomson Molecular Genetics Laboratory, Oxford](https://reader035.vdocument.in/reader035/viewer/2022070307/551b3117550346cf5a8b60f1/html5/thumbnails/9.jpg)
![Page 10: Clinical sensitivity of molecular genetic testing in hypertrophic cardiomyopathy. Kate Thomson Molecular Genetics Laboratory, Oxford](https://reader035.vdocument.in/reader035/viewer/2022070307/551b3117550346cf5a8b60f1/html5/thumbnails/10.jpg)
Gene Protein % of HCM
MYH7 Beta Myosin heavy chain 25-35%
MYBPC3 Myosin-binding protein C 20-30%
TNNT2 Troponin T 3-5%
TNNI3 Troponin I <5%
TPM1 Tropomyosin 1 alpha <2%
MYL3 Regulatory myosin light chain <1%
MYL2 Essential myosin light chain Rare
ACTC1 Actin Rare
Commonly associated sarcomeric genes
![Page 11: Clinical sensitivity of molecular genetic testing in hypertrophic cardiomyopathy. Kate Thomson Molecular Genetics Laboratory, Oxford](https://reader035.vdocument.in/reader035/viewer/2022070307/551b3117550346cf5a8b60f1/html5/thumbnails/11.jpg)
Clinical Sensitivity in HCM• HCM service introduced 2003
• Gene dossier submitted 2006
• Clinical sensitivity estimated to be 60%
• Review clinical sensitivity in cohort (2003-2008)– Determine clinical sensitivity in our cohort (>700 probands)– Comparison with published data– Identify factors affecting clinical sensitivity
![Page 12: Clinical sensitivity of molecular genetic testing in hypertrophic cardiomyopathy. Kate Thomson Molecular Genetics Laboratory, Oxford](https://reader035.vdocument.in/reader035/viewer/2022070307/551b3117550346cf5a8b60f1/html5/thumbnails/12.jpg)
Clinical Sensitivity in our cohort
• 737 probands screened
• 346/737 variant detected
• Clinical sensitivity 47%
![Page 13: Clinical sensitivity of molecular genetic testing in hypertrophic cardiomyopathy. Kate Thomson Molecular Genetics Laboratory, Oxford](https://reader035.vdocument.in/reader035/viewer/2022070307/551b3117550346cf5a8b60f1/html5/thumbnails/13.jpg)
Comparison with published data
• Yield ranged from 13-61%
• 8 most commonly associated genes ~47%
• MYBPC3,MYH7,TNNT2,TNNI3 ~44%
• ~3% increased sensitivity~30% more workload
• 62% family history vs. 29% sporadic
Van Driest et al Mayo Clin Proc 2005
![Page 14: Clinical sensitivity of molecular genetic testing in hypertrophic cardiomyopathy. Kate Thomson Molecular Genetics Laboratory, Oxford](https://reader035.vdocument.in/reader035/viewer/2022070307/551b3117550346cf5a8b60f1/html5/thumbnails/14.jpg)
Factors affecting clinical sensitivity
Clinical sensitivity
ClinicalDiagnosis
AnalysisStrategy
Results interpretation
![Page 15: Clinical sensitivity of molecular genetic testing in hypertrophic cardiomyopathy. Kate Thomson Molecular Genetics Laboratory, Oxford](https://reader035.vdocument.in/reader035/viewer/2022070307/551b3117550346cf5a8b60f1/html5/thumbnails/15.jpg)
Clinical Diagnosis• Exclusion of phenocopies
• Family History
• The future – Refining clinical criteria of “sarcomeric HCM”– Define frequency of phenocopies in HCM cohorts– Cost of clinical vs. genetic investigations
![Page 16: Clinical sensitivity of molecular genetic testing in hypertrophic cardiomyopathy. Kate Thomson Molecular Genetics Laboratory, Oxford](https://reader035.vdocument.in/reader035/viewer/2022070307/551b3117550346cf5a8b60f1/html5/thumbnails/16.jpg)
Analysis strategy• Analysis of less commonly associated genes
• Assay sensitivity and specificity
• New technology (Roche 454)– Expansion of screen– Faster throughput– Results interpretation– Cost implications
![Page 17: Clinical sensitivity of molecular genetic testing in hypertrophic cardiomyopathy. Kate Thomson Molecular Genetics Laboratory, Oxford](https://reader035.vdocument.in/reader035/viewer/2022070307/551b3117550346cf5a8b60f1/html5/thumbnails/17.jpg)
Interpretation of resultsClassification Family testingHighly likely /certain to be pathogenic. Testing available for unaffected family
members (FMs).
Likely to be pathogenic butcannot be formally proven.
Recommend testing affected FMsprior to analysis of unaffected FMs.
Intermediate-not possible todetermine neutral/pathogenic.
Recommend testing affected FMs. Testing unaffected FMs not indicated.
Unlikely to be pathogenic butcannot be formally proven.
Testing FMs not indicated.
Neutral polymorphism-certainly not pathogenic.
Testing FMs not indicated.
![Page 18: Clinical sensitivity of molecular genetic testing in hypertrophic cardiomyopathy. Kate Thomson Molecular Genetics Laboratory, Oxford](https://reader035.vdocument.in/reader035/viewer/2022070307/551b3117550346cf5a8b60f1/html5/thumbnails/18.jpg)
Issues with results interpretation
-the usual suspects……..• High number of private missense mutations
• Functional domains of proteins not defined
• Limited functional studies
• Segregation studies confounded by:– clinical heterogeneity– variable penetrance & age of onset– SCD of other affected FMs
• No clinically normal control cohort
![Page 19: Clinical sensitivity of molecular genetic testing in hypertrophic cardiomyopathy. Kate Thomson Molecular Genetics Laboratory, Oxford](https://reader035.vdocument.in/reader035/viewer/2022070307/551b3117550346cf5a8b60f1/html5/thumbnails/19.jpg)
Clinical sensitivity based on likely pathogenicity
• All 47%• Highly likely & Likely 37%• Highly likely only 27%
Intermediate21%
Likely21%
Highly Likely58%
![Page 20: Clinical sensitivity of molecular genetic testing in hypertrophic cardiomyopathy. Kate Thomson Molecular Genetics Laboratory, Oxford](https://reader035.vdocument.in/reader035/viewer/2022070307/551b3117550346cf5a8b60f1/html5/thumbnails/20.jpg)
In summary• Clinical sensitivity in our cohort 47%
• Several factors thought to impact clinical sensitivity: – Clinical criteria for testing– Analysis strategy chosen– Results interpretation
• Introducing new technology (Roche 454) and techniques (MLPA) to ensure comprehensive analysis
• Hope that future studies will refine clinical criteria and overcome some of the issues with results interpretation
![Page 21: Clinical sensitivity of molecular genetic testing in hypertrophic cardiomyopathy. Kate Thomson Molecular Genetics Laboratory, Oxford](https://reader035.vdocument.in/reader035/viewer/2022070307/551b3117550346cf5a8b60f1/html5/thumbnails/21.jpg)
Acknowledgements
Oxford SCD TeamDr Anneke SellerKaren McGuireMelanie ProvenOmer MohammedJessica ThistletonRia HipkissJohn TaylorSarah ReidPenny Clouston
NHS Department of Clinical GeneticsDr E. Blair